Oligogenic heterozygous inheritance of sperm abnormalities in mouse

Abstract

Male infertility is an important health concern that is expected to have a major genetic etiology. Although high-throughput sequencing has linked gene defects to more than 50% of rare and severe sperm anomalies, less than 20% of common and moderate forms are explained. We hypothesized that this low success rate could at least be partly due to oligogenic defects - the accumulation of several rare heterozygous variants in distinct, but functionally connected, genes. Here, we compared fertility and sperm parameters in male mice harboring one to four heterozygous truncating mutations of genes linked to multiple morphological anomalies of the flagellum (MMAF) syndrome. Results indicated progressively deteriorating sperm morphology and motility with increasing numbers of heterozygous mutations. This first evidence of oligogenic inheritance in failed spermatogenesis strongly suggests that oligogenic heterozygosity could explain a significant proportion of asthenoteratozoospermia cases. The findings presented pave the way to further studies in mice and man.

Data availability

Figure 5 - Source Data 1, Figure 6 - Source Data 1 and Figure 7 - Source Data 1 contain the numerical data used to generate the figures.

Article and author information

Author details

  1. Guillaume Martinez

    CHU Grenoble-Alpes, Grenoble, France
    For correspondence
    gmartinez@chu-grenoble.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7572-9096
  2. Charles Coutton

    CHU Grenoble-Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Corinne Loeuillet

    Institute for Advanced Biosciences, INSERM, CNRS, University Grenoble-Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Caroline Cazin

    CHU Grenoble-Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Jana Muroňová

    Institute for Advanced Biosciences, INSERM, CNRS, University Grenoble-Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Magalie Boguenet

    Institute for Advanced Biosciences, INSERM, CNRS, University Grenoble-Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Emeline Lambert

    Institute for Advanced Biosciences, INSERM, CNRS, University Grenoble-Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Magali Dhellemmes

    Institute for Advanced Biosciences, INSERM, CNRS, University Grenoble-Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Geneviève Chevalier

    Institute for Advanced Biosciences, INSERM, CNRS, University Grenoble-Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Jean-Pascal Hograindleur

    Institute for Advanced Biosciences, INSERM, CNRS, University Grenoble-Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  11. Charline Vilpreux

    Institute for Advanced Biosciences, INSERM, CNRS, University Grenoble-Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  12. Yasmine Neirijnck

    Department of Genetic Medicine and Development, University of Geneva Medical School, Genève, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  13. Zine Eddine Kherraf

    Institute for Advanced Biosciences, INSERM, CNRS, University Grenoble-Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  14. Jessica Escoffier

    Institute for Advanced Biosciences, INSERM, CNRS, University Grenoble-Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8166-5845
  15. Serge Nef

    Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  16. Pierre F Ray

    Institute for Advanced Biosciences, INSERM, CNRS, University Grenoble-Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  17. Christophe Arnoult

    Institute for Advanced Biosciences, INSERM, CNRS, University Grenoble-Alpes, Grenoble, France
    For correspondence
    christophe.arnoult@univ-grenoble-alpes.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3753-5901

Funding

Agence Nationale de la Recherche (ANR-19-CE17-0014)

  • Pierre F Ray
  • Christophe Arnoult

Agence Nationale de la Recherche (ANR-21-CE17-0007)

  • Guillaume Martinez
  • Charles Coutton

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal procedures were conducted according to a protocol approved by the local Ethics Committee (ComEth Grenoble No. 318), by the French government (ministry agreement number #7128 UHTA-U1209-CA), and by the Direction Générale de la Santé (DGS) for the State of Geneva.

Reviewing Editor

  1. Jean-Ju Chung, Yale University, United States

Publication history

  1. Received: November 8, 2021
  2. Preprint posted: November 16, 2021 (view preprint)
  3. Accepted: April 7, 2022
  4. Accepted Manuscript published: April 22, 2022 (version 1)
  5. Version of Record published: May 5, 2022 (version 2)

Copyright

© 2022, Martinez et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Guillaume Martinez
  2. Charles Coutton
  3. Corinne Loeuillet
  4. Caroline Cazin
  5. Jana Muroňová
  6. Magalie Boguenet
  7. Emeline Lambert
  8. Magali Dhellemmes
  9. Geneviève Chevalier
  10. Jean-Pascal Hograindleur
  11. Charline Vilpreux
  12. Yasmine Neirijnck
  13. Zine Eddine Kherraf
  14. Jessica Escoffier
  15. Serge Nef
  16. Pierre F Ray
  17. Christophe Arnoult
(2022)
Oligogenic heterozygous inheritance of sperm abnormalities in mouse
eLife 11:e75373.
https://doi.org/10.7554/eLife.75373
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